Abstract IgE-mediated food allergies have become a major public health concern that now are estimated to affect 6-8% of children under 4 years old and 4% of adults in the US. Approximately 200,000 emergency room visits are caused from allergic reactions to foods annually, with at least 150 fatalities resulting from anaphylaxis. The overall economic cost of food allergies in the US is estimated at $25 billion. There are currently no FDA-approved treatments for food allergies and therefore the only options available to allergic individuals are strict dietary avoidance of the allergen and emergency treatment with epinephrine if a reaction occurs. Allergic reactions to peanuts, tree nuts and shellfish cause the majority of life-threatening anaphylactic food allergy reactions. Shellfish allergies can occur in childhood or adulthood and are typically life-long. Food allergies, including those to shellfish have also increased in prevalence over the past decade. While some treatments, including oral and epicutaneous desensitization therapies, are being clinically evaluated for peanut allergies, there are no rigorous studies being conducted in subjects with shellfish allergies. Therapeutic vaccination is a new and exciting potential treatment option for allergies that requires a considerably abbreviated treatment schedule and may have more profound and longer-lasting effects than desensitization therapies being explored for other food allergies. DNA-based vaccine approaches are among the most promising of the therapeutic vaccination approaches being investigated. In previous studies, we identified a Collaborative Cross mouse strain that can be made allergic to peanuts and tree nuts. Under Specific Aim 1 of this R03, we intend to demonstrate that this same mouse strain can be sensitized to shrimp and other crustacean shellfish. Mice that can be sensitized to shellfish and undergo significant anaphylactic reactions upon subsequent oral challenge with diverse shellfish tissue extracts, will be a useful animal model for us and others to evaluate new therapies for shellfish allergies. Furthermore, we will construct a therapeutic shellfish DNA vaccine, verify that each targeted shellfish allergen is expressed by the vaccine, and then conduct efficacy studies using the vaccine to treat shellfish allergic mice.